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Pharmacogenetics of Drug Metabolism: Overview01:27

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Genetic polymorphism in drug metabolism is crucial to the inter-individual variability observed in drug responses. Drug metabolism primarily involves the chemical modification of drugs and other xenobiotics to enhance their elimination by increasing their polarity. Two main classes of enzymes mediate this biotransformation process: Phase I enzymes, primarily cytochrome P450s, catalyze oxidation and reduction reactions, while other enzymes, such as esterases, mediate hydrolysis, and Phase II...
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Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
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Hepatic impairment, characterized by decreased liver function, does not uniformly mandate adjustments in drug dosage. Whether dosage modifications are necessary depends on various factors related to the drug's metabolism and elimination pathways. If a drug is primarily excreted via the kidneys and bypasses significant hepatic processing, if it undergoes minimal metabolic transformation in the liver, or if it is volatile and primarily expelled through the lungs, dose adjustments may not be...
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Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450...
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The elimination half-life and drug clearance of drugs following nonlinear kinetics can vary with dosage. The Michaelis-Menten parameters and drug concentration influence these factors. As the dose increases, the elimination half-life tends to lengthen, resulting in a reduction in clearance and a disproportionately larger area under the curve. The total clearance can be derived from the Michaelis-Menten equation for drugs following a one-compartment model.
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Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...
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Pharmacogenetic considerations with dichloroacetate dosing.

Margaret O James1, Peter W Stacpoole2,3

  • 1Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, USA.

Pharmacogenomics
|May 5, 2016
PubMed
Summary

Dichloroacetate (DCA) drug dosing is challenging due to metabolic variations. Genetic differences in the glutathione transferase zeta 1 (GSTZ1-1) enzyme affect how individuals process DCA, impacting drug efficacy and safety.

Keywords:
GSTZ1dichloroacetatepharmacogenetics

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Area of Science:

  • Pharmacology and Toxicology
  • Metabolic Medicine
  • Genetics and Personalized Medicine

Background:

  • Dichloroacetate (DCA) is an investigational metabolic regulator used for metabolic diseases and solid tumors.
  • Clinical application of DCA faces challenges in determining optimal dosage regimens.
  • Chronic DCA administration can lead to drug metabolism inhibition and accumulation, causing adverse effects.

Purpose of the Study:

  • To investigate the role of glutathione transferase zeta 1 (GSTZ1-1) in DCA metabolism and pharmacokinetics.
  • To understand how genetic variations in GSTZ1 influence DCA's metabolic fate and inter-individual variability.

Main Methods:

  • Analysis of DCA conversion to glyoxylate, catalyzed by GSTZ1-1.
  • Examination of GSTZ1 enzyme inactivation by DCA.
  • Investigation of single nucleotide polymorphisms (SNPs) in the GSTZ1 gene and their impact on enzyme variants.

Main Results:

  • DCA metabolism is dependent on GSTZ1-1 activity.
  • DCA inactivates GSTZ1-1, leading to potential drug accumulation.
  • GSTZ1 gene polymorphisms result in enzyme variants with differing activities and inactivation rates by DCA.

Conclusions:

  • Inter-individual pharmacokinetic variability of DCA is significantly influenced by GSTZ1 genetic polymorphisms.
  • Understanding GSTZ1 variants is crucial for optimizing DCA dosing and minimizing side effects in clinical practice.
  • This highlights the importance of pharmacogenetics in personalized medicine for DCA therapy.